DE2409971C3 - 5-cholesteric derivatives and process for their preparation - Google Patents

Description

(Ha)

or

OR ⁵

OR ⁴ (I b)

VW '

(Hb)

R ¹ O

wherein R ^{1 is} a hydrogen atom or a lower aliphatic carboxylic acid radical, benzoyl radical or a hydroxyl protecting group and R ² , R ³ , R ⁴ and R ^{5 are} hydrogen, a lower aliphatic carboxylic acid radical and / or benzoyl radical.

2. Process for the preparation of 5-cholestene-30,24,25- or -3 / 3,25,26-triol or its ester of the general formulas

RO

where R is a hydroxyl protecting group in both cases, converts to the corresponding osmate ester, the latter treated with an agent which is capable of causing them to form the corresponding 24,25- or 25,26-dihydroxy compound decompose and that, if necessary, cleavage of the 30-hydroxy protecting group in order to produce the corresponding 3jJ, 24.25- or 3j3,25,56-trihydroxy compound and / or one or more esterified the free hydroxyl groups with an acylating agent.

The invention relates to new 5-cholesteric derivatives and a process for their preparation.

The new 5-cholesteric derivatives according to the invention are represented by the general formulas

OR ²

(Ia)

R ¹ O

OR- ¹ (Ia)

or

R ¹ O

wherein the substituents have the abovementioned meaning, characterized in that osmium tetroxide with R ¹ O protected in the 3 /? position

in which R ^{1 is} a hydrogen atom, a lower aliphatic carboxylic acid radical, a benzoyl radical or a hydroxyl protective group and R, R ¹ , R ⁴ and R ^{5 are} hydrogen and / or a henzoyl radical

mean.

The lower aliphatic carboxylic acid residues derive z. B. of acetyl, propionyl, butyryl and like acids. As used herein, the term "hydroxyl protecting group" is intended to mean any substituent denote commonly used to protect hydroxyl groups on steroid nuclei. Representative examples of such hydroxyl protecting groups are aliphatic or aromatic Hydrocarbon residues, e.g. B. methyl, ethyl and benzyl and carboxylic acid residues, as mentioned above.

Representative examples of new 5-cholestene derivatives according to the invention are given below:

5-cholesten-3 ^ 4,25-triol,

5-Cholesten-3) S, 24,25-triol-3,24,25-triacetate,
5-Choiesten-3ß, 24,25- triol-3,24-diacetate,

30,24-dibenzoate,

5-cholesten-3 ^, 24,25-triol-

30,24,25-tribenzoate,

3 ^ -Methoxy-5-cholestene-24,25-diol,

5-cholesten-3 / 3,25,26-trioi,

5-Cholesten-3] 3,25,26-triol-3-acetate,

5-Cholesien-3 ^, 25,26-triol-3,25,26-tripropionate and

.1 °

.15

40

5-Cholesten-3 ^, 24,25- (or -30,25,2b-) triol and its Esters of the above formulas la or Ib can easily be converted into 24.25- (or 25.26-) dihydroxycholecalciferol and its esters are converted by the following reaction sequence:

1. Bromination to form the 7-bromo derivative,

2. Dehydrobromination to form the 7-dehydro derivative and

3. Exposure to ultraviolet light to form dihydroxycholecalciferol.

It is known that the dihydroxycholecalciferols are metabolites of cholecalciferol, i.e. of vitamin Dj and the active forms of vitamin D ₁ . So far, it has only been possible to obtain these compounds in small amounts by laborious isolation measures from the blood or tissue of animals to which a large amount of cholecalciferol had been administered. The production by a purely chemical process is so far unknown.

Accordingly, the new compounds according to the invention are valuable intermediates for technical purposes Preparation of 24.25- (or 25.26-) dihydroxycholecalciferol.

3j3-Hydroxy-5,24- (or -5,25-) cholestadiene with the formulas

fto

(Ha)

RO

(Hb)

RO

where R in both cases is a hydroxyl protecting group, are the starting materials for the preparation of the compounds according to the invention with the formulas Ia or Ib are used. Some of the Compounds of the formulas Ha and Hb are known, while others are prepared by known methods can be. So z. B. 5,24-cholestadien-3 /? - olacetat of the formula Ha, where R = acetyl, that is Desmosterol acetate and 5,25-cholestadien-3 / S-ol acetate of the formula Hb, where R = acetyl, that is 25-DeHydrocholesterolacetat are formed simultaneously in the mixture, if S-Cholesten-SjS- ^ S-diol-S-acetate, that is, 25-hydroxycholesterol acetate is treated with phosphorus oxychloride. The resulting 5,24-diene and 5,25-diene compounds can be separated from the reaction mixture by preparative thin layer chromatography can be obtained. See J. Lipid Res., 8,152 (1967).

In carrying out the method of the present invention, a protected in the 3jS position is protected 3j3-hydroxy steroid (Ha or lib) initially with Osmium tetroxide implemented in the presence of a solvent. Examples of suitable solvents are Ether, benzene, dioxane, chloroform, carbon tetrachloride, ethyl acetate and mixtures thereof. The reaction temperature and the reaction time are not critical, however, the reaction can usually be carried out at room temperature or below, preferably at room temperature and carried out over a period of several hours to a few days. In this way the osmate ester is obtained, in which a molecule of osmium tetroxide in the double bond between the 24 and 25 or 25 and 26 positions of the starting material has occurred.

After removing the solvent, the resulting ospiate ester is treated with a reagent, which is able to decompose the osmate ester. Any reagents can be used for this purpose known to decompose osmate esters. Representative examples of these reagents are pyridine-aqueous alkali bisulfite, ethanol-aqueous alkali sulfite, mannitol-aqueous alkali hydroxide, zinc-acetic acid, concentrated hydrochloric acid, potassium chlorate-sulfuric acid, chromic acid-acetic acid, formaldehyde-aqueous alkali hydroxide, Hydrogen sulfide and the like.

As a result of the decomposition of the osmate ester, 3 ^ -hydroxy-5-cholesten-24,25- (or 25,26-) diol or the corresponding free 3 /? - hydroxy-steroid depending on the reagent and the used Obtained reaction conditions. Any of the steroid products can pass through from the reaction mixture conventional isolation measures can be isolated.

The 3 ^ -hydroxyl protecting group of the resulting, in 3j3-position protected 3 /? -Hydroxy-steroids is if necessary by conventional measures, e.g. B. by an alkaline hydrolysis, split off, whereby the corresponding free 3j3-hydroxyl compound

dung, i.e. 5-Cholesten-3 / i-2425- (or 3 (3,25,26) triol, is obtained. If desired, the protected 3 ^ -hydroxy-5-cholesten-24 ^ 5- (or 25.26) diol or the corresponding free 3 ^ hydroxyl derivative be further esterified by customary measures, including z. B. an acid anhydride or an acid halide is used. As a result, the mono-, di- or tri-esters of 5-Cholesten-3 ^ -24.25- (or -3fl, 25.26-) triol obtained in which one or more of the free hydroxyl groups in the steroid core and / or in the side chain Acyl radical or the acyl radicals. The invention is illustrated in the following examples.

example 1

1 g desmosterol acetate (or 5,24-cholestadien-3 /? - ol) and 589 mg of osmium tetroxide were suspended in 40 ml of dry ether. The resulting suspension was stirred at room temperature for 19 hours. After distilling off the ether, 60 ml of pyridine, 45 ml Water and 2 g of sodium bisulfite were added and the mixture was left at room temperature for a further 4 hours touched. The resulting reaction mixture was extracted with ether. The essential extract was made washed sequentially with dilute hydrochloric acid and water and on anhydrous sodium sulfate dried and evaporated to dryness. In this way there was 1.008 g of 5-cholesten-3j3-24.25-triol-3,5-acetate obtained, which corresponds to 93.4% of the theoretical yield.

Silica gel thin layer chromatography gave the product a single speck. Melting point 152'C (from Acetone).

Elemental analysis:

C ₂ SH ₄₈ O ₄ (molecular weight 460.67). Calculated: C 75.60, H 10.50%; Found: C 75.34, H 10.56%.

Example 2

100 mg S-Cholesten-SjS ^^ S-triol-SjS-acetate, obtained according to the previous example, in a mixture of 0.3 ml of pyridine and 0.3 ml of acetic anhydride dissolved. After standing overnight, the reaction mixture was poured onto ice water. The resulting crystalline substance was collected by filtration and recrystallized from η-hexane. In this way 5-Cholesten-3] became 3,24,25-triol-3 ^, 24-diacetate obtained with a melting point of 167.5 ° C to 168 ° C (from η-hexane).

Elemental analysis:

C3iH5o0 ₅ (molecular weight 502.71). Calculated: C 74.06, H 10.03%; Found: C 74.22, H 10.03%.

1.10 (611 s'

2, (K) (3 H s

2.08 (3 H s

C-26,27-CH.,)

C-24-CR., CO)

4.70 (2 H d ⁴² O-3. 24-H) 5.35 (I II ηι ^1Λ C-6-H)

In nbiget Aiifslell'.mp hcdeutei:

Ils = SinpliMl.
I 2 ei --- Dublin.
ι λ πι Mulliplctt.

Example 3

500 mg of 5.25-Cho were added to 20 ml of dry ether lesladien-3 / S-olacetate and 295 mg osmium tetroxide given. The resulting reaction mixture was stirred at room temperature for 24 hours. To Distance de ;; 30 ml of pyridine, 22 ml of water and 1 g of sodium bisulfite were successively added to the ether The residue was added and the mixture was stirred at room temperature for 19 hours. The reaction mixture was extracted with ether and the essential extract was diluted with hydrochloric acid and then with Water washed. It was dried over anhydrous sodium sulfate and the solvent became removed by distillation. The obtained crude reaction product was analyzed by thin layer chromatography cleaned on a silica gel block, with a Mixture of benzene and ethyl acetate (10: 1 to 5: 1) eluted. In this way, 380.6 mg of 5-Cholesten-3 /?. 25,26-trioI-3, il acelat obtained, which corresponds to a dent of 70.5% of theory. Mp. 169 ° C to 17 ° C (from ethanol: water).

Elemental analysis:

CmH ₄ BO ₄ (molecular weight 460.67). Calculated: C 75.60. H 10.50%; found: C 75.08, H 10.26%.

NMR " _pm :

1.14 (3 H> ■■ '

2.01 (3 H i.

3.41 (2 H t,

4.60 (1 H m "

5.35 (1 H m

C "-27-CH., L
("-3-CI 1., CO) (-26-CH ₂ )
C-3-H)
C-6-H)

In ohijjer stables means! ¹

-Is = Singkll.
■ ι Im = multiple.

Example 4

500 mg of 5,25-cholestadien-3/3-ol were added to 20 ml of dry ether. acetal and 295 mg osmium tetroxide given. The resulting mixture was stirred at room temperature for 24 hours. After removal of the ether, 30 ml of ethanol, 48 ml of water and 1.47 g of sodium sulfite were added to the residue and the mixture was refluxed for 3 hours. The reaction mixture was washed with ether extracted and the essential extract was washed successively with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting Crude reaction product was purified by chromatography as in Example 3. That way were 336.3 mg S-Cholesten-SjWS ^ ö-triol-S / S-acetate obtained, which corresponds to a yield of 62.3% of theory.

Example 5

100 mg 5-Chc> lesten-3 / ?, 24,25-triol-30-acetate were in 5 ml of a methanol solution of 5% potassium hydroxide for 30 minutes under reflux heated. The reaction solution was diluted with water and then extracted with ethyl acetate. the organic layer of the extract was washed with brine and over anhydrous sodium sulfate dried. After evaporation of the solvent

were 90 mg of 5-Cholesten-3jS, 24,25-triol in the form of a obtained white powder, which has a melting point of 184-187 ° Chatte (from ethyl acetate).

Example 6

100 mg of S-CholestenOj ^ S ^ e-triol-S / J-acetate were hydrolyzed with 5 ml of a 5% methanolic potassium hydroxide solution, with essentially the im Example 5 was followed. There were 90 mg of 5-Cholesten-3j9,25,26-trioI as a white Powder obtained which had a melting point of 180 to 192 ° C (from dimethyl ketone).

Example 7

433 mg of 5-Cholesten-3j3,24,25-triol were dried for one night with 1.0 ml of benzoyl chloride in 2 ml Treated pyridine at room temperature. The reaction mixture was poured into ice water and washed with ether extracted. The extract was sequentially mixed with a 5% sodium hydroxide solution, a 5% hydrochloric acid solution and brine solution washed. After evaporation of the solvent, it became amorphous Powder obtained on silica gel of the general formula

SiO ₂ ■ x \ hO

was chromatographed with a grain size of 0.074 to 0.147 mm (clear mesh size). Elution with a mixture of η-hexane and benzene in a ratio of 1: 1 gave 290 mg of the corresponding tribenzoate in In the form of white crystals with a melting point of 165 to 168 ° C (from dimethyl kelon). One further elution with a mixture of benzene and ethyl acetate in a ratio of 9: 1 gave 457 mg of 5-cholestene-3 / ?, 24,25-triol-3 / J, 24-dibenzoate in the form of white crystals, which have a melting point of 54 to 5b'C had (from dimethyl ketone).

Claims (1)

Patent claims: ! 5-cholesteric derivatives of the general formula OR ² OR ³ (la) ίο 30-hydroxy-5,24- or 5,25-cholestadien-30-ol der general formulas